The present invention relates to novel methods and compositions for the treatment, prevention, or management of sleeplessness, restlessness and weight gain. The methods and compositions utilize plants, portions thereof or extracts therefrom belonging to the Magnoliaceae family. In addition, the methods and compositions utilize mixtures of specific small molecules extracted from the plants belonging to the family Magnoliaceae, such as, but not limited to, magnolol, honokiol, and magnoflorine. The unique compositions of the invention may also comprise various amounts of the Magnoliaceae plant, plant extract, plant extracts combined with different amounts of biologically active small molecules or other therapeutic agents. These compositions are particularly useful for the treatment of sleeplessness, restlessness and weight gain in humans. The invention also encompasses various modes of administration of the therapeutic extracts or other compositions of the invention.
The recent growth in sales of natural products labeled as dietary supplements in the United States has renewed scientific interest in the study of the prophylactic and therapeutic effects of multi-component botanical products. Unlike single entity pharmaceutical products, botanical products comprise a large number of diverse chemical constituents that often act synergistically to exert a desired biological effect. The type of extraction process utilized and the manner in which the formulation is standardized have dramatic effects on the pharmacological activity of the final product. The development of new botanical products requires multidisciplinary effort consisting of expertise in ethnobotany, natural product chemistry, analytical chemistry, pharmacology, and natural product extraction.
Sleep is necessary for survival and good health, but why sleep is needed or exactly how it benefits people is not fully understood. Individual requirements for sleep vary widely; healthy adults may need as few as 4 hours or as many as 9 hours of sleep every day. Most people sleep at night, but many must sleep during the day to accommodate work schedules. This situation often leads to sleep disorders. Most sleep disorders are common.
How long a person sleeps and how rested a person feels on waking can be influenced by may factors, including excitement or emotional distress. Medications also can play a part; some medications make a person sleepy while other makes sleeping difficult. Even some food elements of additives such as caffeine, strong spices, and monosodium glutamate (MSG) may affect sleep.
Sleep is not a uniform state; it has several distinct stages through which it normally cycles five or six times every night. Sleep progresses from stage 1 (the lightest level, during which the sleeper can be awakened easily) to stage 4 (the deepest level, during which waking the sleeper is difficult). In stage 4, the muscles are relaxed, the blood pressure is at the lowest, and the heart and breathing rates are at their slowest. Besides these four stages, there is a form of sleep accompanied by rapid eye movements (REM) and behavioral activity. During REM sleep, electrical activity in the brain is unusually high, somewhat resembling that of wakefulness. The eye movement and brain wave changes that accompany REM sleep can be recorded electrically on an electroencephalogram (EEG).
In REM sleep, the rate and depth of breathing increase, but the muscles are greatly relaxed more so than during the deepest levels of non-REM sleep. Most dreaming occurs during REM and stage 3 sleep, while most talking during sleep, night terrors, and sleepwalking occur during stages 3 and 4. During a normal night""s sleep, REM sleep immediately follows each of the five or six cycles of four-stage non-REM sleep, but it can occur at any of the stages.
If emotional stress is causing the sleep disorder, treatment to relieve the stress is more useful than taking sleep medication. When the sleep disorder is cause by depression, the depression should be thoroughly evaluated and treated by a doctor. Some antidepressant drugs can improve sleep because they have sedating properties. When sleep disorders interfere with a person""s normal activities and sense of well-being, the intermittent use of sleep medications (sedatives, hypnotics) may be useful.
A sedative drug decreases activity, moderates excitement, and calms the recipient, whereas a hypnotic drug produces drowsiness and facilitates the onset and maintenance of a state of sleep that resembles natural sleep in its electroencephalographic characteristics and from which the recipient can be aroused easily. The latter effect sometimes is called hypnosis.
Nonbenozodiazepine sedative-hypnotic drugs belong to a group of agents that depress the central nervous system (CNS) in a relative nonselective, dose-dependent fashion, producing progressively calming or drowsiness (sedation), sleep (pharmacological hypnosis), unconsciousness, coma, surgical anesthesia, and fatal depression of respiration and cardiovascular regulation.
Hypnotics (sedatives, minor tranquilizers, anti-anxiety drugs) are among the most commonly used drugs. Most are quite safe, but all can lose their effectiveness once a person becomes accustomed to them. An undesirable side effect of hypnotics, however, are the withdrawal symptoms when use is discontinued. After more than a few days"" use, discontinuing a hypnotic can make the original sleep problem worse (rebound insomnia) and increase anxiety. Also most hypnotics require a doctor""s prescription because they may be habit-forming or addictive, and overdose is possible. Hypnotics are particularly risky for the elderly and for people with breathing problems because they tend to suppress brain areas that control breathing. They also reduce daytime alertness, making driving or operating machinery hazardous. Hypnotics are especially dangerous when taken with alcohol, other hypnotics, narcotics, antihistamines, and anti-depressants. All of these drugs cause drowsiness and can suppress breathing, making the combined effects more dangerous.
Stress plays a major role in weight management. Stress activates the hypothalamic/pituitary/adrenal axis resulting in an increase in cortisol levels. Cortisol increases the availability of glucose through hepatic gluconeogeneses and the release of glucose substrates from fat cells and muscles. The uptake of glucose is inhibited, resulting in hyperglycemia and hyperlipidemia. The increase in cortisol levels signals the brain that the body is in stress causing food cravings, especially high fat, high sugar foods. These foods, in turn, cause additional stress thereby fueling the stress-cortisol cycle. Eventually, more fat is stored than the body needs unless sufficient exercise is in place to compensate, or the stress is reduced. Central nervous stimulants have been used to suppress appetite in an attempt to counteract stress-induced appetite. This approach not only aggravates the problem due to a direct CNS stimulation effect, but also has a high abuse potential and several serious side effects including cardiovascular and cerebral vascular effects. Ephedra, which is also known as ma huang, is a dietary supplement that is used for weight control and is an example of this type of approach. The purported mechanism of action for Ephedra is CNS stimulation due to the presence of ephedrine alkaloids in the extract.
Extracts from plants belonging to the family Magnoliaceae have been and may still be used in Chinese herbalism. The bark of Magnolia officinalis Rehder et Wilson, xe2x80x9cHou-poxe2x80x9d in Chinese, has been used in Chinese traditional medicine. (Watanabe, K.; Watanabe, H. Y.; Goto, Y.; Yamamoto, N.; Yoshizaki, M.; xe2x80x9cStudies on the Active Principles of Magnolia Bark. Centrally acting Muscle Relaxant Activity of Magnolol and Honokiol,xe2x80x9d Japan. J. Pharmacol. 25, 605 (1975)). Magnolol is the bioactive constituent of Magnolia Cortex, the bark of Magnolia officinalis, Rehd. Et Wils., Magnoliaceae or of M. obvata, Thunb., called wakoboku in Japanese medicine. Honokiol is the bioactive principle isolated from the bark of Magnolia obovata, Thunb., Magnoliaceae and other Magnolia species used in Japanese and Chinese traditional medicine.
The bark of Magnolia officinalis, is reportedly used as an antibacterial, antiseptic, antispasmodic, aphrodisiac, appetizer, digestive, diuretic, emmenagogue, expectorant, ophthalmic, stomachic, and tonic. (Chevalier, A., The Encyclopedia of Medicinal Plants, Dorling Kindersley, London, 1995).
The ether extract of magnolia bark showed a central depressant effect and centrally acting muscle relaxation effect. (Watanabe et al.) Muscle relaxation was shown to be dose-dependent, wherein minimum effective doses required at least 90-100 mg/kg, while sedative symptoms were observed at lower doses. At large doses, honokiol showed a muscle relaxing effect for 3 hours (250 mg/kg) and produced a loss of righting reflex (500 mg/kg). (Watanabe et al. p. 606).
In mice, magnolol produced hypomotility, ptosis, and sedation at 63 mg/kg when administered intraperitoneally. (Watanabe, K.; Watanabe, H.; Goto, Y.; Yamaguchi, M.; Yamamoto, N.; Hagino, K., xe2x80x9cPharmacological Properties of Magnolol and Honokiol Extracted from Magnolia officinalis: Central Depressant Effects,xe2x80x9d Journal of Medicinal Plant Research: Planta Medica, 49, pp. 130-108, (1983)). At a dose of 125 mg/kg magnolol induced sedation, ataxia, and prominent muscle relaxation for 2 hr after injection. Magnolol at a dose of 250 mg/kg produced an ataxia within 10 min, loss of righting reflex in 40 min, and muscle relaxation over 3 hr. Honokiol produced similar effects at doses of 125, 250, and 500 mg/kg i.p. Id.
To date, there are a number of sleep disorders for which there is no dietary supplement available to either prevent or alleviate the disorder or symptoms associated therewith. It is desirable to discover and develop dietary supplements or pharmaceutical compositions based upon natural materials that are both safe and effective. It is particularly desirable to develop plant extracts for the prevention, treatment, or control of sleeplessness, restlessness and weight gain do to stress or lack of sleep.
The invention described herein encompasses compositions and methods of treating or preventing sleeplessness, restlessness or weight gain including, but not limited to, weight gain due to stress or lack of sleep. The methods comprise the administration of a therapeutically or prophylactically effective amount of an extract from the Magnoliaceae family, particularly to a human in need of such therapy. The plants belonging to the Magnoliaceae family include, but are not limited to, plants belonging to the genus Liriodendron and Magnolia. Species belonging to the Liriodendron genus include Liriodendron tulipifera and Liriodendron chinense. Species belonging to the Magnolia genus include, but are not limited to, Magnolia acuminata, Magnolia ashei, Magnolia biodii, Magnolia cylindrica, Magnolia cambellii, Magnolia denudata, Magnolia fraseri, Magnolia grandiflora, Magnolia hypoleuca, Magnolia kobus, Magnolia liliiflora, Magnolia loegneri, Magnolia macrophylla, Magnolia officinalis, Magnolia pyramidata, Magnolia sargentiana, Magnolia seiboldii, Magnolia soulangiana, Magnolia sprengeri, Magnolia stellata, Magnolia tripetala, Magnolia virginiana, Magnolia zenii, and Michelia figo. The extracts of the invention are prepared using solvents such as lower alcohols, water, and mixtures thereof.
Preferably, the compositions comprise Magnoliaceae plant extracts soluble in a lower alcohol, water, and mixtures thereof, or at least two compounds selected from the group consisting of magnolol, honokiol, and magnoflorine. More preferably, the compositions comprise about 2% of honokiol by weight. The compositions may contain a pharmaceutically acceptable carrier, excipient, or diluent. The compositions can be included as unit dosage suitable for parenteral, oral, or intravenous administration to a human. Alternatively, the compositions are dietary supplements, food compositions or beverage compositions suitable for human or animal consumption.
The Magnoliaceae plant extract is obtained by cutting or pulverizing a plant of the family Magnoliaceae, extracting the cut or powdered plant parts with a suitable aqueous solvent for a time sufficient to form an extract. Subsequently, the extract is concentrated under reduced pressure and optionally dried. Further, the extract may optionally be purified to remove undesirable components.
The methods described herein comprise methods for treating, preventing, and managing sleeplessness, restlessness, or both by administering a therapeutically effective amount of a plant extract or a composition comprising a Magnoliaceae plant or plant extract, wherein the Magnoliaceae plant belongs to the genus Liriodendron or Magnolia. The method of treating the above mentioned conditions includes administering an extract obtained using a solvent selected from the group consisting of a lower alcohol, water, and mixtures thereof. Alternatively, the extract comprises at least two compounds selected from the group consisting of magnolol, honokiol, magnoflorine and pharmaceutically acceptable salts thereof. Preferably, the extracts or compositions thereof comprise at least 2% honokiol by weight, and more preferably 2% honokiol.
As used herein, unless otherwise specified, the term xe2x80x9cMagnoliaceae plantxe2x80x9d includes, but is not limited to, any part of a plant within the family Magnoliaceae. The plant parts may include plant bodies preferably the stalk, leaves, fruit or rind, bark, flowers, stems, roots, or seeds. Preferred plants within the Magnoliaceae family are discussed below.
As used herein, unless otherwise specified, the term xe2x80x9ctreating sleeplessnessxe2x80x9d or xe2x80x9ctreatment of sleeplessnessxe2x80x9d includes, but is not limited to, preventing or reducing the disturbances in falling asleep, staying asleep, duration of sleep, or abnormal sleep behaviors.
As used herein, unless otherwise specified, the term xe2x80x9ctreating restlessnessxe2x80x9d, xe2x80x9ctreatment of restlessnessxe2x80x9d or xe2x80x9cpreventing restlessnessxe2x80x9d includes, but is not limited to, causing to rest or relax preferably without inducing sedation or hypnosis, inducing relaxation without inducing muscle relaxation, and relieving nervous tension or stress. Thus, the invention also encompasses methods of inducing relaxation without reduction or loss of motor function in humans.
As used herein, unless otherwise specified, the term xe2x80x9cmanaging weight gainxe2x80x9d includes, but is not limited to, treating, preventing or reducing weight gain, suppressing appetite and in a preferred embodiment treating, preventing or reducing weight gain associated with stress or lack of sleep.
As used herein, unless otherwise specified, the term xe2x80x9cphysiologically acceptable carrier,xe2x80x9d includes, but is not limited to, a carrier medium that does not interfere with the effectiveness of the biological activity of any active ingredients, is chemically inert, and is not toxic to the consumer or patient to whom it is administered.
As used herein, unless otherwise specified, the term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refers to salts prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic and organic acids and bases.
As used herein, unless otherwise specified, the term xe2x80x9cpreventing,xe2x80x9d includes, but is not limited to, inhibition or the averting of symptoms associated with a particular disease or disorder.
As used herein, unless otherwise specified, the term xe2x80x9ctreatingxe2x80x9d refers to the administration of the composition after the onset of symptoms of the disease or disorder whereas xe2x80x9cpreventingxe2x80x9d refers to the administration prior to the onset of the symptoms, particularly to patients at risk of the disease or disorder.
As used herein, unless otherwise specified, the term xe2x80x9clower alcoholxe2x80x9d includes, but is not limited to, straight chained or branched, substituted or unsubstituted hydrocarbon compounds having at least one hydroxyl group and having one to five carbon atoms. Lower alcohols include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, butanols, and mixtures thereof.
As used herein, unless otherwise specified, the term xe2x80x9cobesexe2x80x9d includes, but is not limited to, a person having a Body Mass Index (B MI) of greater than or equal to about 26.
As used herein, unless otherwise specified, the term xe2x80x9caverage weightxe2x80x9d or xe2x80x9cof average weightxe2x80x9d includes, but is not limited to, a person having a Body Mass Index (BMI) of less than about 26.